bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021–10–03
fifty-five papers selected by
Ayesh Seneviratne, University of Toronto
  1. Recreating the Bone Marrow Microenvironment to Model Leukemic Stem Cell Quiescence.
  2. Predictors of Biological Age: The Implications for Wellness and Aging Research.
  3. Chromatin remodeling subunit BRM and valine regulate hematopoietic stem/progenitor cell function and self-renewal via intrinsic and extrinsic effects.
  4. Evidence that overnight fasting could extend healthy lifespan.
  5. GlyNAC Supplementation Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Aging Hallmarks, Metabolic Defects, Muscle Strength, Cognitive Decline, and Body Composition: Implications for Healthy Aging.
  6. HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells.
  7. Autophagy and the Hallmarks of Aging.
  8. Aging, obesity, sarcopenia and the effect of diet and exercise intervention.
  9. Editorial: Clinical Evaluation Criteria for Aging and Aging-Related Multimorbidity.
  10. Effects of High Dietary Carbohydrate and Lipid Intake on the Lifespan of C. elegans.
  11. Cross-Sectional, Short-, Medium-, and Long-Term Effects of Dietary Pattern on Frailty in Taiwan.
  12. Restriction of Dietary Advanced Glycation end Products Induces a Differential Plasma Metabolome and Lipidome Profile.
  13. Frailty in inflammatory bowel diseases: an emerging concept.
  14. Inflammation Suppresses Patients' Ability to Metabolize Cytochrome P450 Substrate Drugs.
  15. CXCR1/2 Inhibitor Ladarixin Ameliorates the Insulin Resistance of 3T3-L1 Adipocytes by Inhibiting Inflammation and Improving Insulin Signaling.
  16. Accelerated Aging as a Paradigm to Understand the Late Effects of Cancer Therapies.
  17. Assessing the Physiological Effects of Traditional Regional Diets Targeting the Prevention of Cardiovascular Disease: A Systematic Review of Randomized Controlled Trials Implementing Mediterranean, New Nordic, Japanese, Atlantic, Persian and Mexican Dietary Interventions.
  18. Lipid Metabolite Biomarkers in Cardiovascular Disease: Discovery and Biomechanism Translation from Human Studies.
  19. The Importance of Age in the Prediction of Mortality by a Frailty Index: A Machine Learning Approach in the Irish Longitudinal Study on Ageing.
  20. Analysis of the Impact of Selected Vitamins Deficiencies on the Risk of Disability in Older People.
  21. Phenol Biological Metabolites as Food Intake Biomarkers, a Pending Signature for a Complete Understanding of the Beneficial Effects of the Mediterranean Diet.
  22. Intermittent and Periodic Fasting, Hormones, and Cancer Prevention.
  23. Mutational patterns and their correlation to CHIP-related mutations and age in hematological malignancies.
  24. Preconditioned Mesenchymal Stromal Cells to Improve Allotransplantation Outcome.
  25. Metabolism modulates network synchrony in the aging brain.
  26. Health Canada: optimizing transparency and its impact for patients.
  27. Annexin A1 as a Regulator of Immune Response in Cancer.
  28. Covid-19 Breakthrough Infections in Vaccinated Health Care Workers.
  29. Covid-19 Breakthrough Infections in Vaccinated Health Care Workers. Reply.
  30. Closing Canada's COVID-19 vaccination gap.
  31. Cisd2 Preserves the Youthful Pattern of the Liver Proteome during Natural Aging of Mice.
  32. Potential Biomarkers for Defining the Severity, Progression, and Survival from COVID-19.
  33. Aging and Cancer: The Waning of Community Bonds.
  34. Prevalence and Correlates of Healthy Aging Among Elderly Aged 65 Years and Over - 6 PLADs, China, 2019.
  35. Using health promotion to support healthy ageing.
  36. Metabolomics activity screening of T cell-induced colitis reveals anti-inflammatory metabolites.
  37. Association between cardiovascular disease- and inflammation-related serum biomarkers and poor lung function in elderly.
  38. Higher DNA repair in mitochondria of long-lived species.
  39. Immune signatures underlying post-acute COVID-19 lung sequelae.
  40. Booster shots for COVID-19-the debate continues.
  41. Nuclear detox of unsaturated fat.
  42. Anti-Inflammatory Effect of Muscle-Derived Interleukin-6 and Its Involvement in Lipid Metabolism.
  43. An overview of chia seed (Salvia hispanica L.) bioactive peptides' derivation and utilization as an emerging nutraceutical food.
  44. National decline in asthma exacerbations in US during COVID19 pandemic.
  45. Neutralizing a Springboard for Inflammation: Physical Activity to Control the Immune Network.
  46. Reverse cardio-oncology: Exploring the effects of cardiovascular disease on cancer pathogenesis.
  47. Prevalence and determinants of frailty in older adult patients with chronic coronary syndrome: a cross-sectional study.
  48. The association of social frailty with intrinsic capacity in community-dwelling older adults: a prospective cohort study.
  49. The Mediterranean Diet as a Source of Natural Compounds: Does It Represent a Protective Choice against Cancer?
  50. Are Dietary Proteins the Key to Successful Body Weight Management? A Systematic Review and Meta-Analysis of Studies Assessing Body Weight Outcomes after Interventions with Increased Dietary Protein.
  51. Nicotinamide Riboside Neutralizes Hypothalamic Inflammation and Increases Weight Loss Without Altering Muscle Mass in Obese Rats Under Calorie Restriction: A Preliminary Investigation.
  52. The metabolite GLP-1 (9-36) is neuroprotective and anti-inflammatory in cellular models of neurodegeneration.
  53. Integrating Research into Community Practice - Toward Increased Diversity in Clinical Trials.
  54. Effects of High-Fat and High-Fat/High-Sucrose Diet-Induced Obesity on PVAT Modulation of Vascular Function in Male and Female Mice.
  55. Ketones - Potential to Achieve Brain Energy Rescue and Sustain Cognitive Health during Aging.
  1. Front Cell Dev Biol. 2021 ;9 662868
    Recreating the Bone Marrow Microenvironment to Model Leukemic Stem Cell Quiescence.
    Eimear O'Reilly, Hojjat Alizadeh Zeinabad, Caoimhe Nolan, Jamileh Sefy, Thomas Williams, Marina Tarunina, Diana Hernandez, Yen Choo, Eva Szegezdi.
      The main challenge in the treatment of acute myeloid leukemia (AML) is relapse, as it has no good treatment options and 90% of relapsed patients die as a result. It is now well accepted that relapse is due to a persisting subset of AML cells known as leukemia-initiating cells or leukemic stem cells (LSCs). Hematopoietic stem cells (HSCs) reside in the bone marrow microenvironment (BMM), a specialized niche that coordinates HSC self-renewal, proliferation, and differentiation. HSCs are divided into two types: long-term HSCs (LT-HSCs) and short-term HSCs, where LT-HSCs are typically quiescent and act as a reserve of HSCs. Like LT-HSCs, a quiescent population of LSCs also exist. Like LT-HSCs, quiescent LSCs have low metabolic activity and receive pro-survival signals from the BMM, making them resistant to drugs, and upon discontinuation of therapy, they can become activated and re-establish the disease. Several studies have shown that the activation of quiescent LSCs may sensitize them to cytotoxic drugs. However, it is very difficult to experimentally model the quiescence-inducing BMM. Here we report that culturing AML cells with bone marrow stromal cells, transforming growth factor beta-1 and hypoxia in a three-dimensional system can replicate the quiescence-driving BMM. A quiescent-like state of the AML cells was confirmed by reduced cell proliferation, increased percentage of cells in the G0 cell cycle phase and a decrease in absolute cell numbers, expression of markers of quiescence, and reduced metabolic activity. Furthermore, the culture could be established as co-axial microbeads, enabling high-throughput screening, which has been used to identify combination drug treatments that could break BMM-mediated LSC quiescence, enabling the eradication of quiescent LSCs.
    Keywords:  acute myeloid leukemia; bone marrow microenvironment; leukemic stem cell; quiescence; three-dimensional model
    DOI:  https://doi.org/10.3389/fcell.2021.662868
  2. Gerontol Geriatr Med. 2021 Jan-Dec;7:7 23337214211046419
    Predictors of Biological Age: The Implications for Wellness and Aging Research.
    Trevor Lohman, Gurinder Bains, Lee Berk, Everett Lohman.
      As healthspan and lifespan research breakthroughs have become more commonplace, the need for valid, practical markers of biological age is becoming increasingly paramount. The accessibility and affordability of biological age predictors that can reveal information about mortality and morbidity risk, as well as remaining years of life, has profound clinical and research implications. In this review, we examine 5 groups of aging biomarkers capable of providing accurate biological age estimations. The unique capabilities of these biomarkers have far reaching implications for the testing of both pharmaceutical and non-pharmaceutical interventions designed to slow or reverse biological aging. Additionally, the enhanced validity and availability of these tools may have increasingly relevant clinical value. The authors of this review explore those implications, with an emphasis on lifestyle modification research, and provide an overview of the current evidence regarding 5 biological age predictor categories: Telomere length, composite biomarkers, DNA methylation "epigenetic clocks," transcriptional predictors of biological age, and functional age predictors.
    Keywords:  aging; biogerontology; cardiovascular diseases and risk; cellular processes; chronic diseases; frailty; genetics
    DOI:  https://doi.org/10.1177/23337214211046419
  3. Leukemia. 2021 Oct 01.
    Chromatin remodeling subunit BRM and valine regulate hematopoietic stem/progenitor cell function and self-renewal via intrinsic and extrinsic effects.
    Samisubbu R Naidu, Maegan Capitano, James Ropa, Scott Cooper, Xinxin Huang, Hal E Broxmeyer.
      Little is known of hematopoietic stem (HSC) and progenitor (HPC) cell self-renewal. The role of Brahma (BRM), a chromatin remodeler, in HSC function is unknown. Bone marrow (BM) from Brm-/- mice manifested increased numbers of long- and short-term HSCs, GMPs, and increased numbers and cycling of functional HPCs. However, increased Brm-/- BM HSC numbers had decreased secondary and tertiary engraftment, suggesting BRM enhances HSC self-renewal. Valine was elevated in lineage negative Brm-/- BM cells, linking intracellular valine with Brm expression. Valine enhanced HPC colony formation, replating of human cord blood (CB) HPC-derived colonies, mouse BM and human CB HPC survival in vitro, and ex vivo expansion of normal mouse BM HSCs and HPCs. Valine increased oxygen consumption rates of WT cells. BRM through CD98 was linked to regulated import of branched chain amino acids, such as valine, in HPCs. Brm-/- LSK cells exhibited upregulated interferon response/cell cycle gene programs. Effects of BRM depletion are less apparent on isolated HSCs compared to HSCs in the presence of HPCs, suggesting cell extrinsic effects on HSCs. Thus, intracellular valine is regulated by BRM expression in HPCs, and the BRM/valine axis regulates HSC and HPC self-renewal, proliferation, and possibly differentiation fate decisions.
    DOI:  https://doi.org/10.1038/s41375-021-01426-8
  4. Nature. 2021 Sep 29.
    Evidence that overnight fasting could extend healthy lifespan.
    Stephen L Helfand, Rafael de Cabo.
      
    Keywords:  Ageing; Metabolism; Nutrition; Physiology
    DOI:  https://doi.org/10.1038/d41586-021-01578-8
  5. J Nutr. 2021 Sep 29. pii: nxab309. [Epub ahead of print]
    GlyNAC Supplementation Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Aging Hallmarks, Metabolic Defects, Muscle Strength, Cognitive Decline, and Body Composition: Implications for Healthy Aging.
    Rajagopal V Sekhar.
      Cellular increases in oxidative stress (OxS) and decline in mitochondrial function are identified as key defects in aging, but underlying mechanisms are poorly understood and interventions are lacking. Defects linked to OxS and impaired mitochondrial fuel oxidation, such as inflammation, insulin resistance, endothelial dysfunction, and aging hallmarks, are present in older humans and are associated with declining strength and cognition, as well as the development of sarcopenic obesity. Investigations on the origins of elevated OxS and mitochondrial dysfunction in older humans led to the discovery that deficiencies of the antioxidant tripeptide glutathione (GSH) and its precursor amino acids glycine and cysteine may be contributory. Supplementation with GlyNAC (combination of glycine and N-acetylcysteine as a cysteine precursor) was found to improve/correct cellular glycine, cysteine, and GSH deficiencies; lower OxS; and improve mitochondrial function, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, and multiple aging hallmarks; and improve muscle strength, exercise capacity, cognition, and body composition. This review discusses evidence from published rodent studies and human clinical trials to provide a detailed summary of available knowledge regarding the effects of GlyNAC supplementation on age-associated defects and aging hallmarks, as well as discussing why GlyNAC supplementation could be effective in promoting healthy aging. It is particularly exciting that GlyNAC supplementation appears to reverse multiple aging hallmarks, and if confirmed in a randomized clinical trial, it could introduce a transformative paradigm shift in aging and geriatrics. GlyNAC supplementation could be a novel nutritional approach to improve age-associated defects and promote healthy aging, and existing data strongly support the need for additional studies to explore the role and impact of GlyNAC supplementation in aging.
    Keywords:  GlyNAC; aging hallmarks; cognition; glutathione; inflammation; insulin resistance; mitochondrial function; oxidative stress; strength
    DOI:  https://doi.org/10.1093/jn/nxab309
  6. Cells. 2021 Sep 09. pii: 2371. [Epub ahead of print]10(9):
    HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells.
    Shen-Han Lee, Monika Golinska, John R Griffiths.
      In solid tumours, cancer cells exist within hypoxic microenvironments, and their metabolic adaptation to this hypoxia is driven by HIF-1 transcription factor, which is overexpressed in a broad range of human cancers. HIF inhibitors are under pre-clinical investigation and clinical trials, but there is evidence that hypoxic cancer cells can adapt metabolically to HIF-1 inhibition, which would provide a potential route for drug resistance. Here, we review accumulating evidence of such adaptions in carbohydrate and creatine metabolism and other HIF-1-independent mechanisms that might allow cancers to survive hypoxia despite anti-HIF-1 therapy. These include pathways in glucose, glutamine, and lipid metabolism; epigenetic mechanisms; post-translational protein modifications; spatial reorganization of enzymes; signalling pathways such as Myc, PI3K-Akt, 2-hyxdroxyglutarate and AMP-activated protein kinase (AMPK); and activation of the HIF-2 pathway. All of these should be investigated in future work on hypoxia bypass mechanisms in anti-HIF-1 cancer therapy. In principle, agents targeted toward HIF-1β rather than HIF-1α might be advantageous, as both HIF-1 and HIF-2 require HIF-1β for activation. However, HIF-1β is also the aryl hydrocarbon nuclear transporter (ARNT), which has functions in many tissues, so off-target effects should be expected. In general, cancer therapy by HIF inhibition will need careful attention to potential resistance mechanisms.
    Keywords:  2-hydroxyglutarate; AMP-activated protein kinase (AMPK); Myc; cancer metabolism; creatine metabolism; glutamine metabolism; glycolysis; hypoxia; hypoxia-inducible factor-1 (HIF-1); lipid metabolism; phosphatidylinositol 3-kinase (PI3K)
    DOI:  https://doi.org/10.3390/cells10092371
  7. Ageing Res Rev. 2021 Sep 23. pii: S1568-1637(21)00215-4. [Epub ahead of print] 101468
    Autophagy and the Hallmarks of Aging.
    Susmita Kaushik, Inmaculada Tasset, Esperanza Arias, Olatz Pampliega, Esther Wong, Marta Martinez-Vicente, Ana Maria Cuervo.
      Autophagy, an essential cellular process that mediates degradation of proteins and organelles in lysosomes, has been tightly linked to cellular quality control for its role as part of the proteostasis network. The current interest in identifying the cellular and molecular determinants of aging, has highlighted the important contribution of malfunctioning of autophagy with age to the loss of proteostasis that characterizes all old organisms. However, the diversity of cellular functions of the different types of autophagy and the often reciprocal interactions of autophagy with other determinants of aging, is placing autophagy at the center of the aging process. In this work, we summarize evidence for the contribution of autophagy to health- and lifespan and provide examples of the bidirectional interplay between autophagic pathways and several of the so-called hallmarks of aging. This central role of autophagy in aging, and the dependence on autophagy of many geroprotective interventions, has motivated a search for direct modulators of autophagy that could be used to slow aging and extend healthspan. Here, we review some of those ongoing therapeutic efforts and comment on the potential of targeting autophagy in aging.
    Keywords:  aging; chaperones; lysosomes; organelle turnover; proteolysis; proteostasis
    DOI:  https://doi.org/10.1016/j.arr.2021.101468
  8. Exp Gerontol. 2021 Sep 22. pii: S0531-5565(21)00343-0. [Epub ahead of print] 111561
    Aging, obesity, sarcopenia and the effect of diet and exercise intervention.
    Georgia Colleluori, Dennis T Villareal.
      The number of adults 65 years and older is increasing worldwide and will represent the 20% of the population by 2030. Half of them will suffer from obesity. The decline in muscle mass and strength, known as sarcopenia, is very common among older adults with obesity (sarcopenic obesity). Sarcopenic obesity is strongly associated with frailty, cardiometabolic dysfunction, physical disability, and mortality. Increasing efforts have been hence made to identify effective strategies able to promote healthy aging and curb the obesity pandemic. Among these, lifestyle interventions consisting of diet and exercise protocols have been extensively explored. Importantly, diet-induced weight loss is associated with fat, muscle, and bone mass losses, and may further exacerbate age-related sarcopenia and frailty outcomes in older adults. Successful approaches to induce fat mass loss while preserving lean and bone mass are critical to reduce the aging- and obesity-related physical and metabolic complications and at the same time ameliorate frailty. In this review article, we discuss the most recent evidence on the age-related alterations in adipose tissue and muscle health and on the effect of calorie restriction and exercise approaches for older adults with obesity and sarcopenia, emphasizing the existing gaps in the literature that need further investigation.
    Keywords:  Adipose tissue; Diet; Elderly; Exercise; Frailty; Lifestyle interventions; Sarcopenia; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.exger.2021.111561
  9. Front Genet. 2021 ;12 764874
    Editorial: Clinical Evaluation Criteria for Aging and Aging-Related Multimorbidity.
    Ilia Stambler, Alexey Moskalev.
      
    Keywords:  aging; biomarkers; clinical endpoints; clinical trials; functional evaluation; longevity; multimorbidity; regulation
    DOI:  https://doi.org/10.3389/fgene.2021.764874
  10. Cells. 2021 Sep 08. pii: 2359. [Epub ahead of print]10(9):
    Effects of High Dietary Carbohydrate and Lipid Intake on the Lifespan of C. elegans.
    Berenice Franco-Juárez, Saúl Gómez-Manzo, Beatriz Hernández-Ochoa, Noemi Cárdenas-Rodríguez, Roberto Arreguin-Espinosa, Verónica Pérez de la Cruz, Daniel Ortega-Cuellar.
      Health and lifespan are influenced by dietary nutrients, whose balance is dependent on the supply or demand of each organism. Many studies have shown that an increased carbohydrate-lipid intake plays a critical role in metabolic dysregulation, which impacts longevity. Caenorhabditis elegans has been successfully used as an in vivo model to study the effects of several factors, such as genetic, environmental, diet, and lifestyle factors, on the molecular mechanisms that have been linked to healthspan, lifespan, and the aging process. There is evidence showing the causative effects of high glucose on lifespan in different diabetic models; however, the precise biological mechanisms affected by dietary nutrients, specifically carbohydrates and lipids, as well as their links with lifespan and longevity, remain unknown. Here, we provide an overview of the deleterious effects caused by high-carbohydrate and high-lipid diets, as well as the molecular signals that affect the lifespan of C. elegans; thus, understanding the detailed molecular mechanisms of high-glucose- and lipid-induced changes in whole organisms would allow the targeting of key regulatory factors to ameliorate metabolic disorders and age-related diseases.
    Keywords:  C. elegans; carbohydrate; lifespan; lipids; transcription factors and metabolism
    DOI:  https://doi.org/10.3390/cells10092359
  11. Int J Environ Res Public Health. 2021 Sep 15. pii: 9717. [Epub ahead of print]18(18):
    Cross-Sectional, Short-, Medium-, and Long-Term Effects of Dietary Pattern on Frailty in Taiwan.
    Mei-Huey Shiau, Meng-Chih Lee, Fang-Ling Lin, Baai-Shyun Hurng, Chih-Jung Yeh.
      This study examined the association between dietary patterns and the development of frailty during 4-, 8-, 12-year follow-up periods in the population-based Taiwan Study. We used the data of an elderly population aged 53 years and over (n = 3486) from four waves of the Taiwan Longitudinal Study on Aging. Frailty was identified by using the modified Fried criteria and the values were summed to derive a frailty score. We applied reduced rank regression to determine dietary patterns, which were divided into tertiles (healthy, general, and unhealthy dietary pattern). We used multinomial logistic regression models to assess the association between dietary patterns and the risk of frailty. The healthy dietary pattern was characterized by a higher intake of antioxidant drinks (tea), energy-rich foods (carbohydrates, e.g., rice, noodles), protein-rich foods (fish, meat, seafood, and eggs), and phytonutrient-rich foods (fruit and dark green vegetables). Compared with the healthy pattern, the unhealthy dietary pattern showed significant cross-sectional, short-term, medium-term, and long-term associations with a higher prevalence of frailty (odds ratios (OR) 2.74; 95% confidence interval (CI) 1.94-3.87, OR 2.55; 95% CI 1.67-3.88, OR 1.66; 95% CI 1.07-2.57, and OR 2.35; 95% CI 1.27-4.34, respectively). Our findings support recommendations to increase the intake of antioxidant drinks, energy-rich foods, protein-rich foods, and phytonutrient-rich foods, which were associated with a non-frail status. This healthy dietary pattern can help prevent frailty over time in elderly people.
    Keywords:  Taiwan; dietary pattern; elderly; frailty; reduced-rank regression
    DOI:  https://doi.org/10.3390/ijerph18189717
  12. Mol Nutr Food Res. 2021 Oct 02. e2000499
    Restriction of Dietary Advanced Glycation end Products Induces a Differential Plasma Metabolome and Lipidome Profile.
    Rebeca Berdún, Mariona Jové, Joaquim Sol, Weijing Cai, John C He, Reyna Rodriguez-Mortera, Meritxell Martin-Garí, Reinald Pamplona, Jaime Uribarri, Manuel Portero-Otin.
       SCOPE: Diets with low content in advanced glycation endproducts (AGEs) lead to beneficial properties in highly prevalent age-related diseases. To shed light on the mechanisms behind, we analyzed the changes induced by a low AGE dietary intervention in the circulating metabolome.
    METHODS AND RESULTS: To this end, 20 non-diabetic patients undergoing peritoneal dialysis were randomized to continue their usual diet or to one with a low content of AGEs for one month. We then analyzed plasmatic metabolome and lipidomes by liquid-chromatography coupled to mass spectrometry. We also quantified the levels of defined AGE structures by ELISA and by mass-spectrometry. The results show that the low AGE diet impinged significant changes in circulating metabolomes (166 molecules) and lipidomes (91 lipids). Metabolic targets of low-AGE intake included sphingolipid, ether-lipids, and glycerophospholipid metabolism. Further, it reproduced some of the plasma characteristics of healthy aging.
    CONCLUSION: The finding of common pathways induced by low-AGE diets with previous metabolic traits implicated in aging, insulin resistance, and obesity, suggest the usefulness of the chosen approach and supports the potential extension of this study to other populations. This article is protected by copyright. All rights reserved.
    Keywords:  ageing; carboxymethyl lysine; ether-lipids; insulin resistance; methylglyoxal; sphingolipids
    DOI:  https://doi.org/10.1002/mnfr.202000499
  13. Therap Adv Gastroenterol. 2021 ;14 17562848211025474
    Frailty in inflammatory bowel diseases: an emerging concept.
    Bharati Kochar, Ariela R Orkaby, Ashwin N Ananthakrishnan, Christine S Ritchie.
      Inflammatory bowel diseases (IBD), consisting of Crohn's disease and ulcerative colitis, are chronic remitting, relapsing inflammatory conditions of the gastrointestinal tract. While traditionally a disease of younger ages, the number of older adults with IBD is rising rapidly. Patients with IBD often experience geriatric syndromes at earlier ages. Older adults with IBD have poorer disease and treatment-related outcomes compared with younger adults with IBD. Applying the principles of geriatrics to understanding a chronic disease in older adults may improve health span. Better tools are needed to stratify IBD patients who are at high risk for adverse events. Frailty is a geriatric construct that may approximate biologic age. Frailty is a complex, multi-dimensional syndrome that leads to increased vulnerability to stress and decline of reserve across multiple physiologic systems. In this review, we present the leading conceptual models of frailty and discuss the applications of frailty in immune-mediated diseases. We also review chronic conditions where frailty has been applied successfully as a tool for risk stratification. Finally, we discuss in the detail the growing body of literature highlighting the relationship between frailty and IBD, the epidemiology of frailty in IBD, and ramifications of frailty in IBD.
    Keywords:  Crohn’s disease; aging; frailty; geriatrics; inflammation; inflammatory bowel diseases; ulcerative colitis
    DOI:  https://doi.org/10.1177/17562848211025474
  14. Ann Pharmacother. 2021 Sep 30. 10600280211047864
    Inflammation Suppresses Patients' Ability to Metabolize Cytochrome P450 Substrate Drugs.
    C Michael White.
       OBJECTIVE: To assess the impact of inflammation on cytochrome P450 (CYP) drug metabolism in human subjects.
    DATA SOURCES: A PubMed search was done from 1980 to July 2021 limited to human subjects and English language using a search strategy of (((phase I metabolism) OR (CYP) OR (cytochrome P450)) AND (inflammatory OR inflammation)).
    STUDY SELECTION AND DATA EXTRACTION: Narrative review of human studies assessing the impact of inflammation or inflammatory suppression with biologic drugs on CYP drug metabolism were used.
    DATA SYNTHESIS: Patients with inflammatory conditions ranging from fungal, viral, or bacterial infections to noninfectious causes (critical illness, surgical procedure, cancer, or transplantation of stem cells or organs) have suppressed drug metabolism. Markers of inflammation such as C-reactive protein or α-1-acid glycoprotein are correlated with reduced clearance through CYP3A4, CYP1A2, and CYP2C19. Elevated interleukin-6 concentrations are also associated or correlated with reduced clearance for CYP3A4 and CYP2C-19 isoenzymes. There was insufficient information to properly assess CYP2D6.
    RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Health professionals should appreciate that patients with acute or chronic inflammation from infectious or noninfectious causes could have suppressed drug metabolism through CYP3A4, CYP1A2, and CYP2C19. For narrow therapeutic index drugs, such as many of the drugs assessed in this review, that means more judicious drug monitoring to prevent adverse events.
    CONCLUSIONS: Like other types of drug-drug or drug-disease interactions, inflammation can alter the steady-state concentration of CYP metabolized drugs.
    Keywords:  drug interactions; inflammation; metabolism
    DOI:  https://doi.org/10.1177/10600280211047864
  15. Cells. 2021 Sep 06. pii: 2324. [Epub ahead of print]10(9):
    CXCR1/2 Inhibitor Ladarixin Ameliorates the Insulin Resistance of 3T3-L1 Adipocytes by Inhibiting Inflammation and Improving Insulin Signaling.
    Vanessa Castelli, Laura Brandolini, Michele d'Angelo, Cristina Giorgio, Margherita Alfonsetti, Pasquale Cocchiaro, Francesca Lombardi, Annamaria Cimini, Marcello Allegretti.
      Type 2 diabetes mellitus is a severe public health issue worldwide. It displays a harmful effect on different organs as the eyes, kidneys and neural cells due to insulin resistance and high blood glucose concentrations. To date, the available treatments for this disorder remain limited. Several reports have correlated obesity with type 2 diabetes. Mainly, dysfunctional adipocytes and the regulation of high secretion of inflammatory cytokines are the crucial links between obesity and insulin resistance. Several clinical and epidemiological studies have also correlated the onset of type 2 diabetes with inflammation, which is now indicated as a new target for type 2 diabetes treatment. Thus, it appears essential to discover new drugs able to inhibit the secretion of proinflammatory adipocytokines in type 2 diabetes. Adipocytes produce inflammatory cytokines in response to inflammation or high glucose levels. Once activated by a specific ligand, CXCR1 and CXCR2 mediate some cytokines' effects by activating an intracellular signal cascade once activated by a specific ligand. Therefore, it is conceivable to hypothesize that a specific antagonist of these receptors may ameliorate type 2 diabetes and glucose metabolism. Herein, differentiated 3T3-L1-adipocytes were subjected to high glucose or inflammatory conditions or the combination of both and then treated with ladarixin, a CXCR1/2 inhibitor. The results obtained point towards the positive regulation by ladarixin on insulin sensitivity, glucose transporters GLUT1 and GLUT4, cytokine proteome profile and lipid metabolism, thus suggesting ladarixin as a potentially helpful treatment in type 2 diabetes mellitus and obesity.
    Keywords:  diabetes; glucose uptake; inflammation; insulin resistance; obesity; pharmacological approach
    DOI:  https://doi.org/10.3390/cells10092324
  16. Front Horm Res. 2021 Sep 24. 54 1-9
    Accelerated Aging as a Paradigm to Understand the Late Effects of Cancer Therapies.
    Saskia Martine Francesca Pluijm.
      Long-term childhood adolescent and young adult (CAYA) cancer survivors may develop health conditions that often coexist at young adulthood or middle age and that normally occur in persons aged 65 years and older, including cardiovascular and musculoskeletal diseases, metabolic syndrome, and secondary malignancies, suggesting that a process of accelerated aging occurs. This chapter summarizes epidemiological evidence and physiological mechanisms of accelerated aging, and possible preventive measures to delay the process of accelerated aging in CAYA cancer survivors. Evidence is mounting that in addition to a high prevalence of specific and multiple aging-related chronic diseases (multimorbidity), CAYA cancer survivors seem to also have a higher risk of other aging phenotypes, including frailty, poor physical performance, and changes in body composition (low muscle and high fat mass). Risk factors for these aging phenotypes include treatment-related factors (cranial-spinal radiotherapy, anthracyclines), sociodemographic factors (higher age, female sex, low socioeconomic status), and unhealthy lifestyle factors (i.e., physical inactivity, obesity, smoking, excess alcohol consumption). The process of accelerated aging may be prevented or delayed by adopting and maintaining a healthy lifestyle, so that CAYA cancer survivors may live a life with optimal quality of life after cancer.
    DOI:  https://doi.org/10.1159/000518816
  17. Nutrients. 2021 Aug 30. pii: 3034. [Epub ahead of print]13(9):
    Assessing the Physiological Effects of Traditional Regional Diets Targeting the Prevention of Cardiovascular Disease: A Systematic Review of Randomized Controlled Trials Implementing Mediterranean, New Nordic, Japanese, Atlantic, Persian and Mexican Dietary Interventions.
    Markos Klonizakis, Alex Bugg, Beatrice Hunt, Xenophon Theodoridis, Dimitrios P Bogdanos, Maria G Grammatikopoulou.
      Traditional regional diets are considered as sustainable dietary patterns, while many have been examined with regard to their health benefits. The aim of the present systematic review was to aggerate all evidence on the physiological effects of regional diets among adults at high risk for cardiovascular disease (CVD). Three databases were searched for randomized controlled trials (RCTs) implementing any regional diet (Mediterranean (MedD), Persian, Southern European Atlantic, Japanese, Chinese, new Nordic, or other) while examining cardiovascular risk factors among adults at increased risk. Primary outcomes included anthropometric indices and secondary outcomes involved blood lipid concentrations, glucose metabolism, inflammation and other markers of CVD progression. Twenty RCTs fulfilled the study's criteria and were included in the qualitative synthesis, with the majority implementing a MedD. Adherence to most of the regional diets induced a reduction in the BW and anthropometric indices of the participants. The majority of RCTs with blood pressure endpoints failed to note a significant reduction in the intervention compared to the comparator arm, with the exception of some new Nordic and MedD ones. Despite the interventions, inflammation markers remained unchanged except for CRP, which was reduced in the intervention groups of one new Nordic, the older Japanese, and the Atlantic diet RCTs. With regard to blood lipids, regional diet interventions either failed to induce significant differences or improved selective blood lipid markers of the participants adhering to the experimental regional diet arms. Finally, in the majority of RCTs glucose metabolism failed to improve. The body of evidence examining the effect of regional dietary patterns on CVD risk among high-risk populations, while employing an RCT design, appears to be limited, with the exception of the MedD. More research is required to advocate for the efficacy of most regional diets with regard to CVD.
    Keywords:  NCD; cardiovascular health; hypertension; inflammation; medical nutrition therapy; noncommunicable disease; nutrition transition; obesity; sustainable diet; territorial diet
    DOI:  https://doi.org/10.3390/nu13093034
  18. Metabolites. 2021 Sep 14. pii: 621. [Epub ahead of print]11(9):
    Lipid Metabolite Biomarkers in Cardiovascular Disease: Discovery and Biomechanism Translation from Human Studies.
    Peter McGranaghan, Jennifer A Kirwan, Mariel A Garcia-Rivera, Burkert Pieske, Frank Edelmann, Florian Blaschke, Sandeep Appunni, Anshul Saxena, Muni Rubens, Emir Veledar, Tobias Daniel Trippel.
      Lipids represent a valuable target for metabolomic studies since altered lipid metabolism is known to drive the pathological changes in cardiovascular disease (CVD). Metabolomic technologies give us the ability to measure thousands of metabolites providing us with a metabolic fingerprint of individual patients. Metabolomic studies in humans have supported previous findings into the pathomechanisms of CVD, namely atherosclerosis, apoptosis, inflammation, oxidative stress, and insulin resistance. The most widely studied classes of lipid metabolite biomarkers in CVD are phospholipids, sphingolipids/ceramides, glycolipids, cholesterol esters, fatty acids, and acylcarnitines. Technological advancements have enabled novel strategies to discover individual biomarkers or panels that may aid in the diagnosis and prognosis of CVD, with sphingolipids/ceramides as the most promising class of biomarkers thus far. In this review, application of metabolomic profiling for biomarker discovery to aid in the diagnosis and prognosis of CVD as well as metabolic abnormalities in CVD will be discussed with particular emphasis on lipid metabolites.
    Keywords:  biomarkers; cardiovascular disease; heart failure; lipidomics; metabolomics
    DOI:  https://doi.org/10.3390/metabo11090621
  19. Geriatrics (Basel). 2021 Aug 27. pii: 84. [Epub ahead of print]6(3):
    The Importance of Age in the Prediction of Mortality by a Frailty Index: A Machine Learning Approach in the Irish Longitudinal Study on Ageing.
    Sebastian Moguilner, Silvin P Knight, James R C Davis, Aisling M O'Halloran, Rose Anne Kenny, Roman Romero-Ortuno.
      The quantification of biological age in humans is an important scientific endeavor in the face of ageing populations. The frailty index (FI) methodology is based on the accumulation of health deficits and captures variations in health status within individuals of the same age. The aims of this study were to assess whether the addition of age to an FI improves its mortality prediction and whether the associations of the individual FI items differ in strength. We utilized data from The Irish Longitudinal Study on Ageing to conduct, by sex, machine learning analyses of the ability of a 32-item FI to predict 8-year mortality in 8174 wave 1 participants aged 50 or more years. By wave 5, 559 men and 492 women had died. In the absence of age, the FI was an acceptable predictor of mortality with AUCs of 0.7. When age was included, AUCs improved to 0.8 in men and 0.9 in women. After age, deficits related to physical function and self-rated health tended to have higher importance scores. Not all FI variables seemed equally relevant to predict mortality, and age was by far the most relevant feature. Chronological age should remain an important consideration when interpreting the prognostic significance of an FI.
    Keywords:  age distribution; frailty; longitudinal studies; mortality; sex differences; supervised machine learning
    DOI:  https://doi.org/10.3390/geriatrics6030084
  20. Nutrients. 2021 Sep 10. pii: 3163. [Epub ahead of print]13(9):
    Analysis of the Impact of Selected Vitamins Deficiencies on the Risk of Disability in Older People.
    Wassim Gana, Arnaud De Luca, Camille Debacq, Fanny Poitau, Pierre Poupin, Amal Aidoud, Bertrand Fougère.
      Vitamin deficiencies have a serious impact on healthy aging in older people. Many age-related disorders have a direct or indirect impact on nutrition, both in terms of nutrient assimilation and food access, which may result in vitamin deficiencies and may lead to or worsen disabilities. Frailty is characterized by reduced functional abilities, with a key role of malnutrition in its pathogenesis. Aging is associated with various changes in body composition that lead to sarcopenia. Frailty, aging, and sarcopenia all favor malnutrition, and poor nutritional status is a major cause of geriatric morbidity and mortality. In the present narrative review, we focused on vitamins with a significant risk of deficiency in high-income countries: D, C, and B (B6/B9/B12). We also focused on vitamin E as the main lipophilic antioxidant, synergistic to vitamin C. We first discuss the role and needs of these vitamins, the prevalence of deficiencies, and their causes and consequences. We then look at how these vitamins are involved in the biological pathways associated with sarcopenia and frailty. Lastly, we discuss the critical early diagnosis and management of these deficiencies and summarize potential ways of screening malnutrition. A focused nutritional approach might improve the diagnosis of nutritional deficiencies and the initiation of appropriate clinical interventions for reducing the risk of frailty. Further comprehensive research programs on nutritional interventions are needed, with a view to lowering deficiencies in older people and thus decreasing the risk of frailty and sarcopenia.
    Keywords:  disability; frailty; malnutrition; micronutrients; older; rehabilitation; sarcopenia; vitamins
    DOI:  https://doi.org/10.3390/nu13093163
  21. Nutrients. 2021 Aug 31. pii: 3051. [Epub ahead of print]13(9):
    Phenol Biological Metabolites as Food Intake Biomarkers, a Pending Signature for a Complete Understanding of the Beneficial Effects of the Mediterranean Diet.
    Juana I Mosele, Maria-Jose Motilva.
      The Mediterranean diet (MD) has become a dietary pattern of reference due to its preventive effects against chronic diseases, especially relevant in cardiovascular diseases (CVD). Establishing an objective tool to determine the degree of adherence to the MD is a pending task and deserves consideration. The central axis that distinguishes the MD from other dietary patterns is the choice and modality of food consumption. Identification of intake biomarkers of commonly consumed foods is a key strategy for estimating the degree of adherence to the MD and understanding the protective mechanisms that lead to a positive impact on health. Throughout this review we propose potential candidates to be validated as MD adherence biomarkers, with particular focus on the metabolites derived from the phenolic compounds that are associated with the consumption of typical Mediterranean plant foods. Certain phenolic metabolites are good indicators of the intake of specific foods, but others denote the intake of a wide-range of foods. For this, it is important to emphasise the need to increase the number of dietary interventions with specific foods in order to validate the biomarkers of MD adherence. Moreover, the identification and quantification of food phenolic intake biomarkers encouraging scientific research focuses on the study of the biological mechanisms in which polyphenols are involved.
    Keywords:  Mediterranean diet; food intake biomarkers; metabolomics; phenol metabolites; polyphenols
    DOI:  https://doi.org/10.3390/nu13093051
  22. Cancers (Basel). 2021 Sep 13. pii: 4587. [Epub ahead of print]13(18):
    Intermittent and Periodic Fasting, Hormones, and Cancer Prevention.
    Giulia Salvadori, Mario Giuseppe Mirisola, Valter D Longo.
      The restriction of proteins, amino acids or sugars can have profound effects on the levels of hormones and factors including growth hormone, IGF-1 and insulin. In turn, these can regulate intracellular signaling pathways as well as cellular damage and aging, but also multisystem regeneration. Both intermittent (IF) and periodic fasting (PF) have been shown to have both acute and long-term effects on these hormones. Here, we review the effects of nutrients and fasting on hormones and genes established to affect aging and cancer. We describe the link between dietary interventions and genetic pathways affecting the levels of these hormones and focus on the mechanisms responsible for the cancer preventive effects. We propose that IF and PF can reduce tumor incidence both by delaying aging and preventing DNA damage and immunosenescence and also by killing damaged, pre-cancerous and cancer cells.
    Keywords:  DNA damage; aging; cancer prevention; fasting; growth hormones
    DOI:  https://doi.org/10.3390/cancers13184587
  23. Blood Adv. 2021 Sep 27. pii: bloodadvances.2021004668. [Epub ahead of print]
    Mutational patterns and their correlation to CHIP-related mutations and age in hematological malignancies.
    Anna Stengel, Constance Baer, Wencke Walter, Manja Meggendorfer, Wolfgang Kern, Torsten Haferlach, Claudia Haferlach.
      Acquired somatic mutations are crucial for the development of the majority of cancers. We performed a comprehensive comparative analysis of the mutational landscapes and their correlation to CHIP-related (clonal hematopoiesis of indeterminate potential) mutations and patient age of 122 genes in 3096 cases with 28 different hematological malignancies. Differences were observed regarding (i) the median number of mutations (highest, median n=4: aCML, CMML, MDS/MPN-U, s-AML; lowest, n=0, CML, MLN-eo, MGUS, PPBL), (ii) specificity of certain mutations (high frequencies in e.g. aCML (ASXL1, 86%), FL (KMT2D, 87%; CREBBP, 73%), HCL (BRAF, 100%), LPL (MYD88, 98%; CXCR4, 51%), MPN (JAK2, 68%)), (iii) distribution of mutations (broad distribution within/across the myeloid/lymphoid lineage e.g. for TET2, ASXL1, DNMT3A, TP53, BCOR, ETV6), (iv) correlation of mutations to patient age (correlated to older age across entites: e.g. TET2, DNMT3A, ASXL1, TP53, EZH2, BCOR, GATA2, IDH2; younger age: e.g. KIT, POT1, RAD21, U2AF2; WT1), (v) correlation of mutation number per patient with age (total cohort (p<0.001), AML (p<0.001), B-ALL (p=0.015), CLL (0.039), MDS (p<0.001), MPN (p<0.001), T-ALL (p=0.005)). Moreover, we observed high frequencies of mutations in RUNX1, SRSF2, IDH2, NRAS, EZH2 in cases comprising at least one DTA mutation (DNMT3A, TET2, ASXL1), while in cases without DTA mutations TP53, KRAS, WT1, SF3B1 were more frequent across entities, suggesting differences in pathophysiology. These results give further insight into the complex genetic landscape and the role of DTA mutations in hematological neoplasms and define mutation-driven entities (MDS/MPN overlap, s-AML) in comparison to entities defined by chromosomal fusions (CML, MLN-eo).
    DOI:  https://doi.org/10.1182/bloodadvances.2021004668
  24. Cells. 2021 Sep 06. pii: 2325. [Epub ahead of print]10(9):
    Preconditioned Mesenchymal Stromal Cells to Improve Allotransplantation Outcome.
    Hui-Yun Cheng, Madonna Rica Anggelia, Cheng-Hung Lin, Chih-Fan Lin.
      Mesenchymal stromal cells (MSCs) are tissue-derived progenitor cells with immunomodulatory as well as multilineage differentiation capacities, and have been widely applied as cellular therapeutics in different disease systems in both preclinical models and clinical studies. Although many studies have applied MSCs in different types of allotransplantation, the efficacy varies. It has been demonstrated that preconditioning MSCs prior to in vivo administration may enhance their efficacy. In the field of organ/tissue allotransplantation, many recent studies have shown that preconditioning of MSCs with (1) pretreatment with bioactive factors or reagents such as cytokines, or (2) specific gene transfection, could prolong allotransplant survival and improve allotransplant function. Herein, we review these preconditioning strategies and discuss potential directions for further improvement.
    Keywords:  allotransplantation; mesenchymal stromal cells; preconditioning
    DOI:  https://doi.org/10.3390/cells10092325
  25. Proc Natl Acad Sci U S A. 2021 Oct 05. pii: e2025727118. [Epub ahead of print]118(40):
    Metabolism modulates network synchrony in the aging brain.
    Corey Weistuch, Lilianne R Mujica-Parodi, Rostam M Razban, Botond Antal, Helena van Nieuwenhuizen, Anar Amgalan, Ken A Dill.
      Brain aging is associated with hypometabolism and global changes in functional connectivity. Using functional MRI (fMRI), we show that network synchrony, a collective property of brain activity, decreases with age. Applying quantitative methods from statistical physics, we provide a generative (Ising) model for these changes as a function of the average communication strength between brain regions. We find that older brains are closer to a critical point of this communication strength, in which even small changes in metabolism lead to abrupt changes in network synchrony. Finally, by experimentally modulating metabolic activity in younger adults, we show how metabolism alone-independent of other changes associated with aging-can provide a plausible candidate mechanism for marked reorganization of brain network topology.
    Keywords:  aging; criticality; fMRI; neurometabolism; synchrony
    DOI:  https://doi.org/10.1073/pnas.2025727118
  26. CMAJ. 2021 Sep 27. 193(38): E1503
    Health Canada: optimizing transparency and its impact for patients.
    Elia Abi-Jaoude, Joel Lexchin.
      
    DOI:  https://doi.org/10.1503/cmaj.80084
  27. Cells. 2021 Aug 30. pii: 2245. [Epub ahead of print]10(9):
    Annexin A1 as a Regulator of Immune Response in Cancer.
    Thaise Gonçalves Araújo, Sara Teixeira Soares Mota, Helen Soares Valença Ferreira, Matheus Alves Ribeiro, Luiz Ricardo Goulart, Lara Vecchi.
      Annexin A1 is a 37 kDa phospholipid-binding protein that is expressed in many tissues and cell types, including leukocytes, lymphocytes and epithelial cells. Although Annexin A1 has been extensively studied for its anti-inflammatory activity, it has been shown that, in the cancer context, its activity switches from anti-inflammatory to pro-inflammatory. Remarkably, Annexin A1 shows pro-invasive and pro-tumoral properties in several cancers either by eliciting autocrine signaling in cancer cells or by inducing a favorable tumor microenvironment. Indeed, the signaling of the N-terminal peptide of AnxA1 has been described to promote the switching of macrophages to the pro-tumoral M2 phenotype. Moreover, AnxA1 has been described to prevent the induction of antigen-specific cytotoxic T cell response and to play an essential role in the induction of regulatory T lymphocytes. In this way, Annexin A1 inhibits the anti-tumor immunity and supports the formation of an immunosuppressed tumor microenvironment that promotes tumor growth and metastasis. For these reasons, in this review we aim to describe the role of Annexin A1 in the establishment of the tumor microenvironment, focusing on the immunosuppressive and immunomodulatory activities of Annexin A1 and on its interaction with the epidermal growth factor receptor.
    Keywords:  Annexin A1; cancer aggressiveness; immune-suppression; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells10092245
  28. N Engl J Med. 2021 Sep 29. pii: 10.1056/NEJMc2113497#sa1. [Epub ahead of print]385(17):
    Covid-19 Breakthrough Infections in Vaccinated Health Care Workers.
    Jiwon Jung, Heungsup Sung, Sung-Han Kim.
      
    DOI:  https://doi.org/10.1056/NEJMc2113497
  29. N Engl J Med. 2021 Sep 29. pii: 10.1056/NEJMc2113497#sa2. [Epub ahead of print]385(17):
    Covid-19 Breakthrough Infections in Vaccinated Health Care Workers. Reply.
    Sharon Amit, Tal Gonen, Gili Regev-Yochay.
      
    DOI:  https://doi.org/10.1056/NEJMc2113497
  30. CMAJ. 2021 09 27. 193(38): E1505-E1506
    Closing Canada's COVID-19 vaccination gap.
    Diana Duong.
      
    DOI:  https://doi.org/10.1503/cmaj.1095963
  31. Biomedicines. 2021 Sep 15. pii: 1229. [Epub ahead of print]9(9):
    Cisd2 Preserves the Youthful Pattern of the Liver Proteome during Natural Aging of Mice.
    Chen-Hua Huang, Yi-Long Huang, Zhao-Qing Shen, Chao-Hsiung Lin, Ting-Fen Tsai.
      Cisd2 (CDGSH iron sulfur domain 2) is a pro-longevity gene that extends the lifespan and health span of mice, ameliorates age-associated structural damage and limits functional decline in multiple tissues. Non-alcoholic fatty liver disease (NAFLD), which plays an important role in age-related liver disorders, is the most common liver disease worldwide. However, no medicines that can be used to specifically and effectively treat NAFLD are currently approved for this disease. Our aim was to provide pathological and molecular evidence to show that Cisd2 protects the liver from age-related dysregulation of lipid metabolism and protein homeostasis. This study makes four major discoveries. Firstly, a persistently high level of Cisd2 protects the liver from age-related fat accumulation. Secondly, proteomics analysis revealed that Cisd2 ameliorates age-related dysregulation of lipid metabolism, including lipid biosynthesis and β-oxidation, in mitochondria and peroxisomes. Thirdly, Cisd2 attenuates aging-associated oxidative modifications of proteins. Finally, Cisd2 regulates intracellular protein homeostasis by maintaining the functionality of molecular chaperones and protein synthesis machinery. Our proteomics findings highlight Cisd2 as a novel molecular target for the development of therapies targeting fatty liver diseases, and these new therapies are likely to help prevent subsequent malignant progression to cirrhosis and hepatocellular carcinoma.
    Keywords:  Cisd2; aging; lipid metabolism; mitochondria; non-alcoholic fatty liver disease; protein homeostasis
    DOI:  https://doi.org/10.3390/biomedicines9091229
  32. Int J Prev Med. 2021 ;12 85
    Potential Biomarkers for Defining the Severity, Progression, and Survival from COVID-19.
    Chidiebere Emmanuel Okechukwu.
      
    DOI:  https://doi.org/10.4103/ijpvm.IJPVM_444_20
  33. Cells. 2021 Aug 31. pii: 2269. [Epub ahead of print]10(9):
    Aging and Cancer: The Waning of Community Bonds.
    Ezio Laconi, Samuele Cheri, Maura Fanti, Fabio Marongiu.
      Cancer often arises in the context of an altered tissue landscape. We argue that a major contribution of aging towards increasing the risk of neoplastic disease is conveyed through effects on the microenvironment. It is now firmly established that aged tissues are prone to develop clones of altered cells, most of which are compatible with a normal histological appearance. Such increased clonogenic potential results in part from a generalized decrease in proliferative fitness, favoring the emergence of more competitive variant clones. However, specific cellular genotypes can emerge with reduced cooperative and integrative capacity, leading to disruption of tissue architecture and paving the way towards progression to overt neoplastic phenotypes.
    Keywords:  aging; cancer; clonal growth; microenvironment; tissue ecology
    DOI:  https://doi.org/10.3390/cells10092269
  34. China CDC Wkly. 2021 Jan 22. 3(4): 69-73
    Prevalence and Correlates of Healthy Aging Among Elderly Aged 65 Years and Over - 6 PLADs, China, 2019.
    Zhaoxue Yin, Xin Gao, Xiaochang Zhang, Xiang Si, Xiaolei Zhu, Jixiang Ma.
       Summary: What is already known on this topic?
    Healthy aging among Chinese older people has low prevalence. Some sociodemographic and lifestyle factors were shown to be associated with healthy aging.
    What is added by this report?
    The age-adjusted prevalence of healthy aging in the 6 provincial-level administrative divisions (PLADs) of China is 15.8 % in 2019. County-level factors, such as the prevalence of healthy communities in a county, as well as some sociodemographic variables and physical exercise, are potential factors of healthy aging.
    What are the implications for public health practice?
    These findings showed that more targeted actions, including generalizing healthy communities and individual-level interventions, may be of great importance for healthy aging.
    DOI:  https://doi.org/10.46234/ccdcw2021.019
  35. Nurs Stand. 2021 Sep 27.
    Using health promotion to support healthy ageing.
    Lesley Hayes, Christine Helen Cartwright.
      Healthy ageing has been defined as the process of developing and maintaining the functional ability that enables well-being in older age. However, as people age, many will develop chronic diseases. Therefore, while life expectancy worldwide has been increasing, this does not necessarily result in a healthy full lifespan, with disability and ill-health often negatively affecting a person's end of life. This article examines the nursing skills required to support older people to live healthy lives against a backdrop of rising levels of chronic conditions. Nurses have a vital role in supporting health improvements in older people by providing targeted solutions such as lifestyle modifications, strengthened social networks and enhanced resilience.
    Keywords:  clinical; health promotion; healthy ageing; lifestyles; older people; public health; well-being
    DOI:  https://doi.org/10.7748/ns.2021.e11693
  36. Sci Signal. 2021 Sep 28. 14(702): eabf6584
    Metabolomics activity screening of T cell-induced colitis reveals anti-inflammatory metabolites.
    J Rafael Montenegro-Burke, Bernard P Kok, Carlos Guijas, Xavier Domingo-Almenara, Clara Moon, Andrea Galmozzi, Seiya Kitamura, Lars Eckmann, Enrique Saez, Gary E Siuzdak, Dennis W Wolan.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/scisignal.abf6584
  37. Clin Proteomics. 2021 Sep 28. 18(1): 23
    Association between cardiovascular disease- and inflammation-related serum biomarkers and poor lung function in elderly.
    K Egervall, A Rosso, S Elmståhl.
       BACKGROUND: Cardiovascular disease (CVD) is a common comorbidity in chronic obstructive pulmonary disease (COPD) and reduced lung function is an important risk factor for CVD and CVD-related death. However, the mechanisms behind the increased risk for CVD in COPD patients are not fully understood.
    METHODS: We examined the association between CVD- and inflammation-related serum biomarkers, and pulmonary function in a geriatric population. 266 biomarkers related to CVD and inflammation were analyzed in blood samples from 611 subjects aged 66-86 years who participated in the Good Aging in Skåne study. Serum levels were assessed by a proximity extension assay. Pulmonary function was measured using the lower limit of normality (LLN) spirometry criteria, i.e., forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC)  <  LLN. Logistic regression models were implemented and multiple comparisons were accounted for.
    RESULTS: 10.3% of the study participants fulfilled pulmonary function decline criteria according to LLN. Out of the 266 biomarkers, only plasminogen activator, urokinase receptor (PLAUR) was statistically significantly associated with decreased pulmonary function. We could not find a statistically significant association between pulmonary function decline and other biomarkers previously linked to COPD, such as interleukin 6, tumor necrosis factor and surfactant protein D.
    CONCLUSION: We found that serum levels of PLAUR are associated with pulmonary function decline in older adults. PLAUR is activated following inflammation and promotes matrix metallopeptidase (MMP) activation and extracellular matrix (ECM) degradation. This implies that PLAUR could play a role in the early phase of COPD pathogenesis.
    Keywords:  Cardiovascular disease; Inflammation; Lung function decline; Proteomics
    DOI:  https://doi.org/10.1186/s12014-021-09329-7
  38. Aging (Albany NY). 2021 Sep 27. undefined(undefined):
    Higher DNA repair in mitochondria of long-lived species.
    Gustavo Barja.
      
    Keywords:  DNA repair; aging rate; base excision repair; longevity; mitochondria
    DOI:  https://doi.org/10.18632/aging.203595
  39. Sci Immunol. 2021 Sep 30. eabk1741
    Immune signatures underlying post-acute COVID-19 lung sequelae.
    I S Cheon, C Li, Y M Son, N P Goplen, Y Wu, T Cassmann, Z Wang, X Wei, J Tang, Y Li, H Marlow, S Hughes, L Hammel, T M Cox, E Goddery, K Ayasoufi, D Weiskopf, J Boonyaratanakornkit, H Dong, H Li, R Chakraborty, A J Johnson, E Edell, J J Taylor, M H Kaplan, A Sette, B J Bartholmai, R Kern, R Vassallo, J Sun.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/sciimmunol.abk1741
  40. Lancet Infect Dis. 2021 10;pii: S1473-3099(21)00574-0. [Epub ahead of print]21(10): 1359-1360
    Booster shots for COVID-19-the debate continues.
    Talha Burki.
      
    DOI:  https://doi.org/10.1016/S1473-3099(21)00574-0
  41. Dev Cell. 2021 Sep 27. pii: S1534-5807(21)00683-3. [Epub ahead of print]56(18): 2539-2541
    Nuclear detox of unsaturated fat.
    Philip J Mannino, C Patrick Lusk.
      Fatty acid saturation in phospholipid bilayers alters their fluidity; whether saturation impacts inner nuclear membrane function has never been addressed. In this issue of Developmental Cell, Romanauska and Köhler (2021) show that the inner nuclear membrane detoxifies itself of unsaturated fatty acids by shunting them into cytosolic lipid droplets.
    DOI:  https://doi.org/10.1016/j.devcel.2021.09.002
  42. Int J Mol Sci. 2021 Sep 13. pii: 9889. [Epub ahead of print]22(18):
    Anti-Inflammatory Effect of Muscle-Derived Interleukin-6 and Its Involvement in Lipid Metabolism.
    Hidetoshi Nara, Rin Watanabe.
      Interleukin (IL)-6 has been studied since its discovery for its role in health and diseases. It is one of the most important pro-inflammatory cytokines. IL-6 was reported as an exacerbating factor in coronavirus disease. In recent years, it has become clear that the function of muscle-derived IL-6 is different from what has been reported so far. Exercise is accompanied by skeletal muscle contraction, during which, several bioactive substances, collectively named myokines, are secreted from the muscles. Many reports have shown that IL-6 is the most abundant myokine. Interestingly, it was indicated that IL-6 plays opposing roles as a myokine and as a pro-inflammatory cytokine. In this review, we discuss why IL-6 has different functions, the signaling mode of hyper-IL-6 via soluble IL-6 receptor (sIL-6R), and the involvement of soluble glycoprotein 130 in the suppressive effect of hyper-IL-6. Furthermore, the involvement of a disintegrin and metalloprotease family molecules in the secretion of sIL-6R is described. One of the functions of muscle-derived IL-6 is lipid metabolism in the liver. However, the differences between the functions of IL-6 as a pro-inflammatory cytokine and the functions of muscle-derived IL-6 are unclear. Although the involvement of myokines in lipid metabolism in adipocytes was previously discussed, little is known about the direct relationship between nonalcoholic fatty liver disease and muscle-derived IL-6. This review is the first to discuss the relationship between the function of IL-6 in diseases and the function of muscle-derived IL-6, focusing on IL-6 signaling and lipid metabolism in the liver.
    Keywords:  IL-6; NAFLD; exercise; gp130; myokine; soluble IL-6R
    DOI:  https://doi.org/10.3390/ijms22189889
  43. Front Biosci (Landmark Ed). 2021 Sep 30. 26(9): 643-654
    An overview of chia seed (Salvia hispanica L.) bioactive peptides' derivation and utilization as an emerging nutraceutical food.
    Roshina Rabail, Moazzam Rafiq Khan, Hafiza Mahreen Mehwish, Muhammad Shahid Riaz Rajoka, Jose Manuel Lorenzo, Marek Kieliszek, Abdur Rauf Khalid, Muhammad Asim Shabbir, Rana Muhammad Aadil.
      Chia (S. hispanica L.) is an annual herbaceous plant that has gained popularity for its seeds of high-quality vegetative proteins, richest contents of omega-3 polyunsaturated fatty acids (Ω-3 PUFA), soluble dietary fiber, and great gelling ability, as well as its high contents of bioactive peptides of antioxidative and nutraceutical potential for many other clinical biomarkers. Such health protective bioactive peptides should be utilized for supplementation in the food and nutrition industries. This review was therefore designed to align the researches done on chia bioactive peptide's derivation, processing, consumption and to identify their antioxidative and nutraceutical potential for various disease biomarkers. The evidence gathered is fairly compelling for the health-promising nutraceutical and clinical potential of chia seed bioactive peptides as antioxidants, dipeptidyl peptidase-IV inhibitors (DPP4), angiotensin-converting enzyme (ACE) inhibitors, and anti-inflammatory drugs. Their assimilation into everyday diets has the potential to open new doors in health departments and food sectors.
    Keywords:  Antihypertensive; Antiinflammatory; Antioxidative; Chia bioactive peptides; Chia hydrolysates
    DOI:  https://doi.org/10.52586/4973
  44. Ann Allergy Asthma Immunol. 2021 Sep 25. pii: S1081-1206(21)01113-3. [Epub ahead of print]
    National decline in asthma exacerbations in US during COVID19 pandemic.
    Regina W Lam, Jonathan W Inselman, Molly M Jeffery, Jacob T Maddux, Matthew A Rank.
      
    DOI:  https://doi.org/10.1016/j.anai.2021.09.017
  45. Healthcare (Basel). 2021 Sep 10. pii: 1196. [Epub ahead of print]9(9):
    Neutralizing a Springboard for Inflammation: Physical Activity to Control the Immune Network.
    Victor Kallen, Rogier Scherder, Maarten J Cramer, Jacqueline Stam, Bruce Johnson, Erik Scherder.
      The severe consequences of the present Corona Virus Disease 2019 COVID-19 pandemic seem to be closely related to an already ongoing ('first') pandemic, directly associated with a sedentary lifestyle. It seems evident that the prognosis after infection is substantially worse for individuals suffering from, for example, (visceral) obesity, cardiovascular disease, and diabetes type 2. Consequently, it may be considered highly relevant to gain insight into the potential beneficial effects of exercise interventions to strengthen the immune system, particularly in high-risk populations. For this reason, the exercise protocols that are suggested to strengthen the immune system, which can be executed by all ages and almost all physical conditions, were reviewed and evaluated. Previously published protocols range from interrupting prolonged sitting, to regular low-to-moderate exercise activities, to high intensity, typically interval, sports formats. Reported positive effects on immune functioning appear to be induced either directly or via beneficial metabolic and/or psychological effects and become measurable after 3 weeks to 3 months. Based in these findings, it appeared possible to design an optimal exercise protocol to maximize effects on immune functioning that should be executable for all, even under restricted ('lockdown') circumstances.
    Keywords:  COVID-19; exercise; immune functioning; inflammation; lifestyle; sedentary; stress
    DOI:  https://doi.org/10.3390/healthcare9091196
  46. J Mol Cell Cardiol. 2021 Sep 25. pii: S0022-2828(21)00180-2. [Epub ahead of print]
    Reverse cardio-oncology: Exploring the effects of cardiovascular disease on cancer pathogenesis.
    Graeme J Koelwyn, Joseph Pierre Aboumsallem, Kathryn J Moore, Rudolf A de Boer.
      The field of cardio-oncology has emerged in response to the increased risk of cardiovascular disease (CVD) in patients with cancer. However, recent studies suggest a more complicated CVD-cancer relationship, wherein development of CVD, either prior to or following a cancer diagnosis, can also lead to increased risk of cancer and worse outcomes for patients. In this review, we describe the current evidence base, across epidemiological as well as preclinical studies, which supports the emerging concept of 'reverse-cardio oncology', or CVD-induced acceleration of cancer pathogenesis.
    Keywords:  Cancer progression; Cancer risk; Cardio-oncology; Cardiovascular disease
    DOI:  https://doi.org/10.1016/j.yjmcc.2021.09.008
  47. BMC Geriatr. 2021 Sep 30. 21(1): 519
    Prevalence and determinants of frailty in older adult patients with chronic coronary syndrome: a cross-sectional study.
    Hong Lyu, Chuanxia Wang, Hong Jiang, Ping Wang, Jingjing Cui.
       BACKGROUND: Frailty is an expression of vulnerability and decline of physical, mental, and social activities, more commonly found in older adults. It is also closely related to the occurrence and poor prognosis of coronary artery disease (CAD). Little investigation has been conducted on the prevalence and determinants of frailty in older adult patients with chronic coronary syndrome (CCS).
    METHODS: A cross-sectional study was conducted, simple random sampling was used in this study. 218 older adults (age ≥ 60 years) with CCS with an inpatient admission number ending in 6 were randomly selected who hospitalized in Department of Geriatric Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, China, between January and December 2018. For measurement and assessment, we used the 5-item FRAIL scale (fatigue, resistance, ambulation, illnesses, and loss of weight), demographic characteristics, Barthel Index(BI), Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS-15), Mini Nutrition Assessment Shor-Form (MNA-SF), Morse Fall Scale (MFS), Caprini risk assessment, polypharmacy, and Numerical Rating Scale (NRS). Multivariate logistic regression analysis was used to confirme determinants.
    RESULTS: The FRAIL scale showed 30.3% of the subjects suffered from frailty. Determinants were aging (OR1.12; 95% CI 1.04 ~ 1.62), out-of-pocket (OR18.93; 95% CI 1.11 ~ 324.07), hearing dysfunction (OR9.43; 95% CI 1.61 ~ 55.21), MNA-SF score (OR0.71; CI 0.57 ~ 0.89), GDS-15 score (OR1.35; 95% CI 1.11 ~ 1.64), and Caprini score (OR1.34; 95% CI 1.06 ~ 1.70).
    CONCLUSIONS: The FRAIL scale confirmed that the prevalence of frailty in patients with CCS was slightly lower than CAD. Aging, malnutrition, hearing dysfunction, depression, and VTE risk were significantly associated with frail for older adult patients with CCS. A comprehensive assessment of high-risk patients can help identify determinants for frailty progression. In the context of CCS, efforts to identify frailty are needed, as are interventions to limit or reverse frailty status in older CCS patients.
    Keywords:  Chronic coronary syndrome; Determinants; Frailty; Older adult patients; Prevalence
    DOI:  https://doi.org/10.1186/s12877-021-02426-0
  48. BMC Geriatr. 2021 Sep 27. 21(1): 515
    The association of social frailty with intrinsic capacity in community-dwelling older adults: a prospective cohort study.
    Chi Hsien Huang, Kiwako Okada, Eiji Matsushita, Chiharu Uno, Shosuke Satake, Beatriz Arakawa Martins, Masafumi Kuzuya.
       BACKGROUND: Social frailty is associated with poor health outcomes; however, its effects on healthy aging indicators have not been adequately investigated. This study assessed the longitudinal association between social frailty and the intrinsic capacity of community-dwelling older adults.
    METHODS: A total of 663 participants (56.7% women) aged ≥60 years from in Nagoya, Japan, were included in the study. The first measurement occurred in 2014, and annual follow-ups occurred until 2017. Social frailty was determined based on four items: financial difficulty, household status, social activity, and regular contact with others. A deficit score of 0 represented social robustness, 1 represented social prefrailty, and ≥ 2 represented social frailty. Intrinsic capacity was evaluated by the locomotion, cognition, psychological function, vitality, and sensory function domains. The longitudinal association was analyzed using generalized estimating equations.
    RESULTS: The prevalence of social prefrailty and social frailty at baseline was 31.2 and 6.3%, respectively. The social prefrailty group (β = - 0.132, P < 0.001) and social frailty group (β = - 0.258, P < 0.001) were associated with a greater reduction in the composite intrinsic capacity scores than the social robustness group, especially in the cognition, psychological function, and vitality domains. Men with social prefrailty/social frailty demonstrated a greater decrease in the psychological function domain score (- 0.512 vs. - 0.278) than women. Additionally, the cognition domain score only decreased in men in the social prefrailty/social frailty group (β = - 0.122, P = 0.016).
    CONCLUSIONS: Social frailty was associated with intrinsic capacity and its subdomains longitudinally. Men with social frailty were more vulnerable than women to a decline in their psychological function and cognition domains. Therefore, the advanced management of social frailty is necessary to facilitate healthy aging.
    Keywords:  Cognition; Healthy aging; Psychological function; Successful aging; Vitality
    DOI:  https://doi.org/10.1186/s12877-021-02466-6
  49. Pharmaceuticals (Basel). 2021 Sep 11. pii: 920. [Epub ahead of print]14(9):
    The Mediterranean Diet as a Source of Natural Compounds: Does It Represent a Protective Choice against Cancer?
    Giuseppina Augimeri, Daniela Bonofiglio.
      The Mediterranean diet (MD), characterized by a high intake of fruits, vegetables, legumes, nuts and grains, a moderate intake of red wine and a reduced consumption of meat, has been considered one of the healthiest dietary patterns worldwide. Growing evidence suggests an inverse relationship between high adherence to the MD and cancer, as well as other chronic degenerative diseases. The beneficial effects elicited by the MD pattern on cancer are due to the high contents of bioactive compounds contained in many foods of MD, which protect cells by oxidative and inflammatory processes and inhibit carcinogenesis by targeting the various hallmarks of cancer with different mechanisms of action. Although over the past decades numerous dietary and phytochemical compounds from Mediterranean food that have anticancer potential have been identified, a clear association between the MD eating pattern and cancer needs to be established. While we wait for answers to this question from well-conducted research, the empowering of the MD as a protective choice against cancer should represent the priority for public health policies.
    Keywords:  Mediterranean Diet; cancer incidence; cancer prevention; healthy eating
    DOI:  https://doi.org/10.3390/ph14090920
  50. Nutrients. 2021 Sep 14. pii: 3193. [Epub ahead of print]13(9):
    Are Dietary Proteins the Key to Successful Body Weight Management? A Systematic Review and Meta-Analysis of Studies Assessing Body Weight Outcomes after Interventions with Increased Dietary Protein.
    Thea Toft Hansen, Arne Astrup, Anders Sjödin.
      The primary aim was to systematically review the current evidence investigating if dietary interventions rich in protein lead to improved body weight management in adults with excessive body weight. The secondary aim was to investigate potential modifying effects of phenotyping. A systematic literature search in PubMed, Web of Science, and Cochrane Library identified 375 randomized controlled trials with 43 unique trials meeting the inclusion criteria. The Cochrane collaboration tool was used for a thorough risk of bias assessment. Based on 37 studies evaluating effects of dietary protein on body weight, the participants with increased protein intake (ranging from 18-59 energy percentage [E%]) were found to reduce body weight by 1.6 (1.2; 2.0) kg (mean [95% confidence interval]) compared to controls (isocaloric interventions with energy reduction introduced in certain studies). Individuals with prediabetes were found to benefit more from a diet high in protein compared to individuals with normoglycemia, as did individuals without the obesity risk allele (AA genotype) compared to individuals with the obesity risk alleles (AG and GG genotypes). Thus, diets rich in protein would seem to have a moderate beneficial effect on body weight management.
    Keywords:  appetite; obesity; overweight; satiety; weight loss
    DOI:  https://doi.org/10.3390/nu13093193
  51. Front Nutr. 2021 ;8 648893
    Nicotinamide Riboside Neutralizes Hypothalamic Inflammation and Increases Weight Loss Without Altering Muscle Mass in Obese Rats Under Calorie Restriction: A Preliminary Investigation.
    Josimar Macedo de Castro, Dirson João Stein, Helouise Richardt Medeiros, Carla de Oliveira, Iraci L S Torres.
      Obesity treatments, such as calorie restriction (CR), eventually lead to muscle wasting and higher rates of neuroinflammation, whereas hypothalamic inflammatory conditions impair body weight (BW) control. Nicotinamide riboside (NR) has been proposed against obesity but with little evidence on skeletal muscle tissue (SMT) and neuroinflammation. Therefore, we aimed to investigate the effects of CR on SMT and on hypothalamic inflammatory biomarkers in obese adult male Wistar rats, and whether NR supplementation alone or in combination with CR affects these parameters. Obesity was induced in rats through a cafeteria diet for 6 weeks. After that, a group of obese rats was exposed to CR, associated or not associated with NR supplementation (400 mg/kg), for another 4 weeks. As a result, obese rats, with or without CR, presented lower relative weight of SMT when compared with eutrophic rats. Rats under CR presented lower absolute SMT weight compared with obese and eutrophic rats, in addition to presenting elevated hypothalamic levels of TNF-α. NR supplementation, in all groups, enhanced weight loss and increased relative weight of the SMT. Furthermore, in animals under CR, NR reversed increases TNF-α levels in the hypothalamus. In this study, these data, although succinct, are the first to evidence the effects of NR on SMT and neuroinflammation when associated with CR, especially in obesity conditions. Therefore, this provides preliminary support for future studies in this investigative field. Furthermore, NR emerges as a potential adjuvant for preventing muscle mass loss in the weight loss processes.
    Keywords:  brain; caloric restriction; hypothalamus; muscle mass; neuroinflammation; nicotinamide riboside; obesity; skeletal muscle tissue
    DOI:  https://doi.org/10.3389/fnut.2021.648893
  52. J Neurochem. 2021 Sep 27.
    The metabolite GLP-1 (9-36) is neuroprotective and anti-inflammatory in cellular models of neurodegeneration.
    Yazhou Li, Elliot J Glotfelty, Tobias Karlsson, Lowella V Fortuno, Brandon K Harvey, Nigel H Greig.
      Glucagon-like peptide-1 (GLP-1) is best known for its insulinotropic action following food intake. Its metabolite, GLP-1 (9-36), was assumed biologically inactive due to low GLP-1 receptor (GLP-1R) affinity and non-insulinotropic properties; however, recent studies contradict this assumption. Increased use of FDA approved GLP-1 analogues for treating metabolic disorders and neurodegenerative diseases raises interest in GLP-1 (9-36)'s biological role. We use human SH-SY5Y neuroblastoma cells and a GLP-1R overexpressing variety (#9), in both undifferentiated and differentiated states, to evaluate the neurotrophic/neuroprotective effects of GLP-1 (9-36) against toxic glutamate exposure and other oxidative stress models (via the MTS, LDH or ROS assays). In addition, we examine GLP-1 (9-36)'s signaling pathways, including cyclic-adenosine monophosphate (cAMP), protein kinase-A (PKA), and 5' adenosine monophosphate activated protein kinase (AMPK) via use of ELISA, pharmacological inhibitors, or GLP-1R antagonist. Human HMC3 and mouse IMG microglial cell lines were used to study the anti-inflammatory effects of GLP-1 (9-36) against lipopolysaccharide (LPS) (via ELISA). Finally, we applied GLP-1 (9-36) to primary dissociation cultures challenged with α-synuclein or amyloid-β and assessed survival and morphology via immunochemistry. We demonstrate evidence of GLP-1R, cAMP, PKA, and AMPK mediated neurotrophic and neuroprotective effects of GLP-1 (9-36). The metabolite significantly reduced IL-6 and TNF-α levels in HMC3 and IMG microglial cells, respectively. Lastly, we show mild but significant effects of GLP-1 (9-36) in primary neuron cultures challenged with α-synuclein or amyloid-β. These studies enhance understanding of GLP-1 (9-36)'s effects on the nervous system and its potential as a primary or complementary treatment in pathological contexts.
    Keywords:  Exendin-4; GLP-1; GLP-1 (9-36); neurodegeneration; neuroinflammation; neuroprotection
    DOI:  https://doi.org/10.1111/jnc.15521
  53. N Engl J Med. 2021 Oct 02.
    Integrating Research into Community Practice - Toward Increased Diversity in Clinical Trials.
    Janet Woodcock, Richardae Araojo, Twyla Thompson, Gary A Puckrein.
      
    DOI:  https://doi.org/10.1056/NEJMp2107331
  54. Front Pharmacol. 2021 ;12 720224
    Effects of High-Fat and High-Fat/High-Sucrose Diet-Induced Obesity on PVAT Modulation of Vascular Function in Male and Female Mice.
    Jamaira A Victorio, Daniele M Guizoni, Israelle N Freitas, Thiago R Araujo, Ana P Davel.
      Increased adiposity in perivascular adipose tissue (PVAT) has been related to vascular dysfunction. High-fat (HF) diet-induced obesity models are often used to analyze the translational impact of obesity, but differences in sex and Western diet type complicate comparisons between studies. The role of PVAT was investigated in small mesenteric arteries (SMAs) of male and female mice fed a HF or a HF plus high-sucrose (HF + HS) diet for 3 or 5 months and compared them to age/sex-matched mice fed a chow diet. Vascular responses of SMAs without (PVAT-) or with PVAT (PVAT+) were evaluated. HF and HF + HS diets increased body weight, adiposity, and fasting glucose and insulin levels without affecting blood pressure and circulating adiponectin levels in both sexes. HF or HF + HS diet impaired PVAT anticontractile effects in SMAs from females but not males. PVAT-mediated endothelial dysfunction in SMAs from female mice after 3 months of a HF + HS diet, whereas in males, this effect was observed only after 5 months of HF + HS diet. However, PVAT did not impact acetylcholine-induced relaxation in SMAs from both sexes fed HF diet. The findings suggest that the addition of sucrose to a HF diet accelerates PVAT dysfunction in both sexes. PVAT dysfunction in response to both diets was observed early in females compared to age-matched males suggesting a susceptibility of the female sex to PVAT-mediated vascular complications in the setting of obesity. The data illustrate the importance of the duration and composition of obesogenic diets for investigating sex-specific treatments and pharmacological targets for obesity-induced vascular complications.
    Keywords:  endothelial dysfunction; obesity; perivascular adipose tissue; resistance arteries; sex differences
    DOI:  https://doi.org/10.3389/fphar.2021.720224
  55. Br J Nutr. 2021 Sep 28. 1-47
    Ketones - Potential to Achieve Brain Energy Rescue and Sustain Cognitive Health during Aging.
    Étienne Myette-Côté, Adrian Soto-Mota, Stephen C Cunnane.
      Alzheimer's disease (AD) is the most common major neurocognitive disorder of aging. Although largely ignored until about a decade ago, accumulating evidence suggests that deteriorating brain energy metabolism plays a key role in the development and/or progression of AD-associated cognitive decline. Brain glucose hypometabolism is a well-established biomarker in AD but was mostly assumed to be a consequence of neuronal dysfunction and death. However, its presence in cognitively asymptomatic populations at higher risk of AD strongly suggests that it is actually a pre-symptomatic component in the development of AD. The question then arises as to whether progressive AD-related cognitive decline could be prevented or slowed down by correcting or bypassing this progressive 'brain energy gap'. In this review, we provide an overview of research on brain glucose and ketone metabolism in AD and its prodromal condition - mild cognitive impairment (MCI) - to provide a clearer basis for proposing keto-therapeutics as a strategy for brain energy rescue in AD. We also discuss studies using ketogenic interventions and their impact on plasma ketone levels, brain energetics and cognitive performance in MCI and AD. Given that exercise has several overlapping metabolic effects with ketones, we propose that in combination these two approaches might be synergistic for brain health during aging. As cause-and-effect relationships between the different hallmarks of AD are emerging, further research efforts should focus on optimizing the efficacy, acceptability and accessibility of keto-therapeutics in AD and populations at risk of AD.
    Keywords:  Alzheimer; acetoacetate; beta-hydroxybutyrate; brain function; brain glucose metabolism; cognition; energy metabolism; exercise; glucose control; insulin signaling; ketone; mild cognitive impairment; mitochondrial function
    DOI:  https://doi.org/10.1017/S0007114521003883
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